Targeting Deubiquitinating Enzymes (DUBs) That Regulate Mitophagy via Direct or Indirect Interaction with Parkin

Abstract

The quality control of mitochondria is critical for the survival of cells, and defects in the pathways required for this quality control can lead to severe disease. A key quality control mechanism in cells is mitophagy, which functions to remove damaged mitochondria under conditions of various stresses. Defective mitophagy can lead to a number of diseases including neurodegeneration. It has been proposed that an enhancement of mitophagy can improve cell survival, enhance neuronal function in neurodegeneration and extend health and lifespans. In this review, we highlight the role of deubiquitinating enzymes (DUBs) in the regulation of mitophagy. We summarise the current knowledge on DUBs that regulate mitophagy as drug targets and provide a list of small molecule inhibitors that are valuable tools for the further development of therapeutic strategies targeting the mitophagy pathway in neurodegeneration.

PRKN-linked familial Parkinson’s disease: cellular and molecular mechanisms of disease-linked variants

“…Deubiquitinating enzymes (DUBs), also known as ubiquitin-specific proteases (USPs), mediate this reversal by cleaving isopeptide bonds between individual ubiquitin moieties or between ubiquitin and the protein target [ 121 , 122 ]. Accordingly, DUBs capable of trimming the ubiquitin or phospho-ubiquitin chains on OMM proteins antagonize mitophagy, and are thus obvious drug targets for PD [ 123 – 126 ]. Intriguingly, USP30, a K6-ubiquitin-chain-specific DUB localized on the OMM, has been shown to antagonize Parkin/PINK1-dependent mitophagy by deubiquitinating OMM proteins, including TOM20 [ 127 – 129 ].…”